Principal Investigator
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P11 Alexander Gottschalk
Professor
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Buchmann Institute for Molecular Life Sciences &
Institute of Biochemistry
Goethe-University Frankfurt a.M.
Max-von-Laue-Str. 15
60438 Frankfurt am Main, Germany
Phone +49 (0)69 798-42518
Fax +49 (0)69 798-763 42518
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P11 Channelrhodopsin-2 and Halorhodopsin - optogenetic tools for fast, non-invasive manipulation of neuronal circuits
In the neurosciences, it is of fundamental interest to learn how neural circuits process information to generate behaviour, and the possibility to achieve exogenous control over neuronal activity in vivo would greatly facilitate such studies. Chlamydomonas Channelrhodopsin-2 (ChR2), a blue light-activated cation channel, and Natronomonas Halorhodopsin (NpHR), a yellow light-activated chloride-pump, can be used as optical activators and inhibitors of neurons and other excitable cells in heterologous systems. Work done in this research group, as well as in other labs, demonstrated the use of ChR2 and NpHR for photo-depolarization or -hyperpolarization, respectively, in Caenorhabditis elegans neurons and muscles, in mammalian neurons in culture, brain slices, Drosophila larvae, chick embryos, and in live mice. Yet, certain limitations remain (e.g. need for high expression levels, cell-specificity of expression depending on available promoters, incompatibility with imaging of cell activity, no targeting to subcellular structures or organelles) that hamper the use of these tools to their full potential. By a structure-function approach, we want to extend the potential of ChR2 and NpHR as ‘optogenetic’ tools. We want to engineer reconstitution-competent split versions of ChR2 and NpHR, shift their action spectra, improve their efficiency and achieve sub-cellular localization.
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Fig. 1: Muscle contractions induced in C. elegans by photo-activation of ChR2
Fig. 2: Inhibition of C. elegans swimming behavior induced by photo-activation of NpHR
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Publications
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Schultheis, C., Liewald, J.F., Bamberg, E., Nagel, G., and Gottschalk A. (2011) Optogenetic Long-Term Manipulation of Behavior and Animal Development. PLoS One 6(4): e18766.
Weissenberger S., Schultheis C., Liewald J., Erbguth K., Nagel G., Gottschalk A. (2011) PACa - an optogenetic tool for in vivo manipulation of cellular cAMP levels, neurotransmitter release, and behavior in Caenorhabditis elegans. J Neurochem 116, 616-625.
Stirman, J., Crane, M., Husson, S., Schultheis, C., Gottschalk, A.*, and Lu, H.* (2010) Real-time multimodal optical control of individual neurons and muscles in freely behaving Caenorhabditis elegans. Nature Meth 8, 153-158. (*corresponding authors)
Almedom, R. , Liewald, J.F., Hernando, G., Schultheis, C., Rayes, D., Pan, J., Schedletzky, T., Hutter, H., Bouzat, C., and Gottschalk, A. (2009) An ER-resident membrane protein complex of NRA-2 and NRA-4 regulates nicotinic acetylcholine receptor subunit composition in Caenorhabditis elegans. EMBO J 28, 2636–2649.
Mahoney, T.R., Luo, S.*, Round, E.K., Brauner, M., Gottschalk, A., Thomas, J.H. and Nonet, M.L. (2008) Intestinal Signaling to GABAergic Neurons Regulates a Rhythmic Behavior in C. elegans. PNAS 105, 16350-16355.
Liewald, J.F.*, Brauner, M.*, Stephens, G., Magail Bouhours, Schultheis, C., Mei Zhen and Gottschalk, A. (2008) Optogenetic analysis of synaptic function. Nature Meth 5, 895-902. (*shared first-authorship)
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Collaborations
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Fendler/Bamberg (P10), Forrest (P8), Wachtveitl (P12), Glaubitz (P6), Abele (P9)